The Impact of Bioinformatics on Vaccine Design and Development

Vaccines are the pharmaceutical products that offer the best cost‐benefit ratio in the prevention or treatment of diseases. In that a vaccine is a pharmaceutical product, vaccine development and production are costly and it takes years for this to be accomplished. Several approaches have been applied to reduce the times and costs of vaccine development, mainly focusing on the selection of appropriate antigens or antigenic structures, carriers, and adjuvants. One of these approaches is the incorporation of bioinformatics methods and analyses into vaccine development. This chapter provides an overview of the application of bioinformatics strategies in vaccine design and development, supplying some successful examples of vaccines in which bioinformatics has furnished a cutting edge in their development. Reverse vaccinology, immunoinformatics, and structural vaccinology are described and addressed in the design and development of specific vaccines against infectious diseases caused by bacteria, viruses, and parasites. These include some emerging or re‐emerging infectious diseases, as well as therapeutic vaccines to fight cancer, allergies, and substance abuse, which have been facilitated and improved by using bioinformatics tools or which are under development based on bioinformatics strategies

Vaccination against Trichinella spiralis: Potential, Limitations and Future Directions

Trichinellosis is a food-borne parasitic disease caused by round worms of the genus Trichinella. The majority of human outbreaks are attributed to consumption of raw or undercooked pork meat contaminated with T. spiralis muscle larvae. A blocking-transmission vaccine against trichinellosis will allow preventing swine infection and will contribute to disease control. In this chapter, different vaccine candidates so far developed against T. spiralis, including first-, second-, and third-generation vaccines, are discussed. Most vaccine candidates are based on a unique antigen mainly from the muscle larva stage, inducing with some exceptions, partial protection although a mix Th1/Th2 immune response is elicited. Therefore, the need for identification of new antigens from different parasite stages focusing on infective intestinal larvae, adult, and newborn larvae stages as well as the evaluation of their protective capacity in pigs is presented. The design of multi-epitope vaccines and the use of adjuvants or immunomodulatory molecules capable to polarize the immune response to a Th2-type-protective response are discussed as imperative elements of modern vaccines. Plant-based vaccines and probiotics as excellent tools for vaccine development against T. spiralis are also presented as an attractive platform for veterinary vaccines

A novel gene signature unveils three distinct immune- metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes

Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches

Androgen receptor and its splicing variant 7 expression in peripheral blood mononuclear cells and in circulating tumor cells in metastatic castration-resistant prostate cancer

Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation

Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel's classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients

NEXT-100 Technical Design Report (TDR). Executive Summary

In this Technical Design Report (TDR) we describe the NEXT-100 detector that will search for neutrinoless double beta decay (bbonu) in Xe-136 at the Laboratorio Subterraneo de Canfranc (LSC), in Spain. The document formalizes the design presented in our Conceptual Design Report (CDR): an electroluminescence time projection chamber, with separate readout planes for calorimetry and tracking, located, respectively, behind cathode and anode. The detector is designed to hold a maximum of about 150 kg of xenon at 15 bar, or 100 kg at 10 bar. This option builds in the capability to increase the total isotope mass by 50% while keeping the operating pressure at a manageable level. The readout plane performing the energy measurement is composed of Hamamatsu R11410-10 photomultipliers, specially designed for operation in low-background, xenon-based detectors. Each individual PMT will be isolated from the gas by an individual, pressure resistant enclosure and will be coupled to the sensitive volume through a sapphire window. The tracking plane consists in an array of Hamamatsu S10362-11-050P MPPCs used as tracking pixels. They will be arranged in square boards holding 64 sensors (8 times8) with a 1-cm pitch. The inner walls of the TPC, the sapphire windows and the boards holding the MPPCs will be coated with tetraphenyl butadiene (TPB), a wavelength shifter, to improve the light collection.Comment: 32 pages, 22 figures, 5 table